Squalene and lanosterol are crucial intermediates in steroid biosynthesis. Squalene forms from farnesyl diphosphate, then converts to lanosterol through oxidation and cyclization. These steps involve complex enzymatic reactions and rearrangements, setting the stage for steroid production.

The biosynthesis of squalene and lanosterol showcases nature's elegant chemistry. From the head-to-head joining of farnesyl diphosphate to the intricate cyclization of oxidosqualene, these processes demonstrate the precision of enzymatic catalysis in creating complex biological molecules.

Biosynthesis of Squalene and Lanosterol

Biosynthesis of squalene and lanosterol

• Squalene synthesized from farnesyl diphosphate (FPP) through a series of enzymatic steps catalyzed by squalene synthase
  • Two FPP molecules joined head-to-head manner
  • Diphosphate group eliminated from one FPP molecule forming presqualene diphosphate (PSPP)
  • PSPP undergoes reductive rearrangement NADPH reduces diphosphate group leading to squalene formation
• Squalene converted to lanosterol through two-step process
  • First squalene oxidized by squalene epoxidase forming oxidosqualene (2,3-oxidosqualene)
  • Oxidosqualene undergoes complex cyclization reaction catalyzed by lanosterol synthase forming tetracyclic structure of lanosterol (precursor to cholesterol and other steroids)

Mechanism of squalene epoxidation

• Squalene epoxidase is a flavoprotein monooxygenase catalyzes stereospecific epoxidation of squalene
• Reaction mechanism involves several steps:
  1. Enzyme's flavin cofactor (FAD) reduced by NADPH forming FADH2
  2. Molecular oxygen (O2) binds to reduced flavin forming flavin hydroperoxide intermediate
  3. Oxygen atom from hydroperoxide transferred to terminal double bond of squalene forming oxidosqualene (2,3-oxidosqualene)
  4. Remaining oxygen atom reduced to water regenerating oxidized flavin cofactor (FAD)
• Epoxidation reaction is stereospecific oxygen atom added to si face of terminal double bond in squalene

Cyclization of oxidosqualene to lanosterol

• Cyclization of oxidosqualene to lanosterol catalyzed by enzyme lanosterol synthase
• Reaction involves series of concerted electrophilic additions and carbocation rearrangements:
  1. Epoxide ring of oxidosqualene protonated by enzyme forming carbocation intermediate
  2. Carbocation undergoes series of electrophilic additions forming A, B, and C rings of steroid nucleus
  3. Series of hydride and methyl shifts occur stabilizing carbocation intermediate
  4. D ring formed through final electrophilic addition carbocation quenched by deprotonation step
• Key carbocation rearrangements in cyclization process include:
  • Hydride shift from C-17 to C-20
  • Methyl shift from C-14 to C-13
  • Second hydride shift from C-9 to C-8
• Final product of cyclization is lanosterol serves as precursor for biosynthesis of other steroids (cholesterol, testosterone, estradiol)

Regulation of Steroid Biosynthesis

• Steroid biosynthesis is regulated through the isoprenoid pathway, which includes the mevalonate pathway
• HMG-CoA reductase is a key regulatory enzyme in the mevalonate pathway, controlling the rate-limiting step of cholesterol biosynthesis
• Sterol regulatory element-binding proteins (SREBPs) play a crucial role in regulating gene expression of enzymes involved in steroid biosynthesis
• These regulatory mechanisms ensure proper control of steroid production in response to cellular needs and environmental factors